Biotin, which is variously known as (3a.alpha.,4.beta.,6a.alpha.)-hexahydro-2-oxothieno[3,4-d]imidazole-4-pent anoic acid or vitamin H is a natural product originally isolated from egg yolk and liver. A stereo specific synthesis of d-biotin (Confalone, et al., JACS, 97, 5936 (1975) is known but is not commercially viable. Present commercial production is believed to depend an early patented process disclosed in U.S. Pat. No. 2,489,232. It would be desirable to provide a high yield process using inexpensive starting materials. One total synthetic route is disclosed by Lavielle, et al. (JACS, 100, 1558 (1978)).
An important intermediate in the synthesis of biotin is (3a.alpha.,6a.alpha.)-1,3-dibenzylhexahydro-1H-thieno[3,4-d]imidazol-2(3H) -one 5,5-dioxide whose synthesis is reported by Ohba, et al., Agr. Biol. Chem., 38, 2431 (1974). A synthesis of the dibenzyl derivative thereof is reported by Kotake, et al., Chemistry Letters, 1073 (1976). The problem with the Kotake synthesis is that the first stage yields a mixture of two products which are only separable by column chromatography. The major portion is the trans isomer which is not the desired product. While the conversion of the desired cis-isomer with phosgene affords the (3a.alpha.,6a.alpha.)-1,3-dibenzylhexahydro-1H-thieno[3,4-d]imidazol-2(3H) -one 5,5-dioxide in quantitative yield, the intermediate chromatographic separation step constitutes a substantial barrier in the way of industrial use of the process. It would therefore be desirable to modify the Kotake process in such a way as to either avoid the problem of separation of isomers or at least provide isomeric products which are separable by more industrially viable procedures such as differential crystallization.